Our long term efforts have been directed towards establishing the protective effects of various dietary lipids and decreased calorie intake against the development and acceleration of autoimmune disease (AD) which causes early morbidity and mortality in aging populations. : We recently observed that feeding commonly-consumed dietary fats such as monounsaturated Lard (rich in (18:1) omega-9) or polyunsaturated (PUFA) corn oil (rich in (18:2) (omega-6) promotes AD in NZBxNZWF1 (B/W) female mice, whereas highly polyunsaturated (HUFA) omega-3 fish oil (high in (20:5) and (22:6) (omega-3) with optimum antioxidant supplement exerts a significant protection. A more dramatic effect on inhibition of AD and lengthening of life span was however noted, when we followed a combination of HUFA diet with food restriction (FR). Our working hypothesis is that increased oonsumption of PUFA promotes AD and certain malignancies by inducing elevated levels of endocrine hormones, autoantibodies and several proinflammatory cytokines. We have recently observed that protection against AD can be achieved by FR by inhibiting the rise in memory T cells (PGP-1high) which are known to produce pro-inflammatory cytokines such as IL-4, IL-5, and IL-6. Our proposed studies are therefore directed toward elucidating the immunological mechanism(s) involved in increasing the anti-inflammatory cytokines by following a well-balanced ratio of (omega-6 and o)-3 fatty acids in the diet. We therefore intend to study and compare the effects of diets containing PUFA (18:2) omega-6 and linolenic acid-containing oils such as flax seed oil (18:3 omega-3); and also continued the studies with menhaden fish oil ((omega-3), with and without FR, to define age-associated functional changes in virgin (PGP-1high) and memory (PGP-1high) T cells, B cells and macrophages (M0). Furthermore, production of anti-inflammatory (IL-2, IFN-gamma), pro-inflammatory as well as regulatory (IL-10) cytokines will also be measured by bioassays to compare lymphokine release in activated T lymphocytes and M0. This study will be further parallelled by analysis of mRNA accumulation and protein production both in young and old animals fed HUFA omega-3 and PUFA diets. Also, phospholipid composition and Ca2+ influx in T cell subsets and changes in self-reactive T cell receptor Vp regions in response to Con-A or staphylococcal enterotoxin B will be analyzed. Proposed studies should further contribute to a better understanding of the protective role of dietary factors involving lipids and calorie intake on delaying AD in mice. These findings can be applied to reducing age-related AD phenomena by appropriate long-term dietary interventions to improve the quality of life in the aging population.